The purpose of this proposal is to identify and characterize biochemical markers that assess disease risk and progression. Over the last decade, the quantification of collagenous and noncollagenous macromolecules derived from bone, cartilage, and synovial tissues has gained interest in many areas of basic and clinical research. The further development, evaluation and validation of biomarkers that provide insights into osteoarthritis risk and progression is an important research goal. We plan to conduct small-scale studies within existing longitudinal datasets of knee osteoarthritis studies to evaluate and validate promising biomarkers. Specifically we will assess whether increased levels of cartilage degradation products are predictive of cartilage loss, and whether uncoupling of cartilage synthesis and degradation is predictive of cartilage loss. One of the major changes in the extracellular matrix of cartilage is the age-related accumulation of advanced glycation end products. It remains unknown whether higher levels of AGEs precede and predict cartilage loss. The recognition of AGE accumulation as an important factor in OA may provide new possibilities for prevention and/or therapy via the inhibition and/or reversal of cartilage AGE formation. The structural properties of subchondral bone play a role in the degeneration of cartilage, and these trabecular changes are considered necessary for the progression of OA. It remains unknown whether increased bone remodeling as assessed using biochemical markers of bone formation and resorption is associated with bone marrow edema lesions. As importantly we will explore whether the parameters of bone remodeling among those with bone marrow edema predict cartilage loss, but among those without bone marrow edema, bone remodeling markers do not predict cartilage loss. To accomplish these aims, the combined resources of the only longitudinal natural history OA studies in which MRI's and biological specimens were obtained will be used. We will utilize already collected data from the Boston Osteoarthritis of the Knee Study (BOKS) in which 260 subjects with symptomatic knee OA were followed over an average of 30 months, undergoing during that time 3 comprehensive examinations, each including an MRI and fluoroscopically-positioned radiographs, and for whom biological specimens were collected. We plan to conduct nested case-control studies within this study on knee MRI morphological features of interest. The plan is for the analyses to be conducted in the BOKS study. Where a biomarker demonstrates great potential in these analyses this will subsequently be validated in the Health ABC Study. This proposal has the potential for defining biomarkers that are risk factors and predictors for knee OA progression. Both of these steps are important preliminary steps before a biomarker can be used in therapeutic monitoring. Use of validated biomarkers will greatly accelerate therapeutic development for this pressing public health concern.